My research focuses on the elucidation of factor(s) responsible for the cause or progression of common kidney diseases using molecular genetic approach.
Specifically, my main research interest is autosomal dominant polycystic kidney disease (ADPKD)
which accounts for ~10 % of all cases of end-stage kidney disease. Two major genes (i.e. PKD1 and PKD2) have been identified for this disease and the existence of a third gene (i.e. PKD3) has been recently suggested.
We and other investigators have shown that most mutations in these genes likely result in the complete loss of function of their encoded proteins. Moreover, we and our collaborators have shown that the formation of each cyst in ADPKD requires the inactivation of both copies of a PKD gene (i.e. through one mutation passed through the blood line and a second mutation that is acquired after birth). The acquired mutation is the rate-limiting step for the individual cyst formation.
This 'two-hit' model for cystogenesis strongly implicates that there are additional genetic and environmental factors that determine the frequency of these acquired mutations and therefore, the severity of the cystic disease.
A second major focus of my research involves the identification of gene variants that modify the progression of chronic kidney diseases
. Specifically, we have recently identified specific gene variants in the renin-angiotensin pathway (which modulate both blood pressure and cellular responses to injury) that are risk factors for progressive kidney failure in a common disease called IgA nephropathy.
- To identify the genetic and environmental factors that determine the frequency of the acquired PKD mutations and hence, the severity of cystic disease by studying affected sibling pairs from families with ADPKD. The identification of these factors will be essential for the design of specific therapeutic interventions for this disease.
- To map and identify the third gene (PKD3) for ADPKD. The identification of this disease gene will yield insight into the specific pathway for cyst formation and is also an essential step for the development of specific treatment.
- To identify other genetic factors that promote progressive kidney failure (i.e. genetic modifiers). Such knowledge will help to develop predictive tests for identifying 'high-risk' patients who may benefit from early therapeutic interventions.